Targeting Unstable Genes

Due to instability in the gene, Huntington’s disease symptoms may begin earlier in life. By targeting proteins involved in DNA damage repair, we might be able to reduce the levels of instability and delay disease progression.

Many repair proteins work to maintain the machinery that copies DNA. 

One of these proteins – so-called Huntington’s disease (HD) modifiers – is FAN1. People with slightly different versions of FAN1 protein have huge differences in when their Huntington’s disease symptoms begin. 

According to HDBuzz, experiments carried out by HD geneticists in the United States and United Kingdom, led by Dr. Jong-Min Lee at Harvard Medical School, found that the protein might be slightly better or slightly worse at its repair job depending on the FAN1 gene a person has. 

Normally, these small individual differences won’t matter. However, for a person with Huntington’s disease “excellence in DNA repair is critically important.” 

Hence, FAN1’s ability to repair DNA seems to play a crucial role in the onset of symptoms.

Another repair protein currently being studied is MSH3. Changes in this protein can also affect the age at which people with Huntington’s disease start to get symptoms. 

– A better understanding of the influence of FAN1 and other DNA repair genes on HD is already leading to new therapeutic strategies to improve DNA repair and slow CAG repeat expansion, Dr Rachel Harding and Dr Leora Fox write in the recently published HDBuzz article

CAG repeat expansion and onset of symptoms

Many studies have recently started to connect DNA damage repair to CAG repeat expansion.

From the HDBuzz article, we can learn that DNA is not a fixed blueprint but rather dynamic and adaptable:

– When DNA repair goes awry, repeating sections of the DNA code can become unstable. In the case of Huntington’s disease, this means that over a person’s lifetime, the already-expanded HD gene gains even more CAGs, in certain cells of the brain and body.

The process of gaining even more CAG repeats is known as somatic instability.

Large genetic studies have confirmed that due to somatic instability, Huntington’s disease symptoms may begin earlier in life.

Somatic instability

Everyone with Huntington’s disease has inherited a genetic mutation: an extra-long repetitive stretch of the CAG sequence in the Huntingtin gene. 

A sequence of 36 or more CAG-repetitions results in the production of a protein called mutant huntingtin. This protein is believed to play a crucial role in the progression of Huntington’s disease.

The Huntingtin (HTT) gene contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. CAGCAGCAG). Generally, people have fewer than 36 repetitions. A sequence of 36 or more CAG-repetitions results in the production of a protein which has different characteristics. This altered form is called mutant huntingtin (mHTT). (Photo: Wikipedia)

– The more [CAG] repeats in the huntingtin protein, the more likely it is to perform poorly, form toxic clumps in brain cells, and disrupt other normal functions, Dr Rachel Harding and Dr Leora Fox writes.

That’s why longer CAG repeats are associated with earlier onset of symptoms.

– Now we know that a person with HD whose blood test showed 42 repeats as a young adult, may at the time of their death thirty years later have some cells in the brain with 45, 60, 100, or even 1000 CAG repeats.

– So the formation of longer and longer huntingtin proteins could be part of the reason that HD affects people more as they get older, the two doctors state in the HDBuzz article. 

That’s why DNA damage repair is so important.  

Targeting repair proteins

By targeting proteins involved in DNA damage repair, we might be able to reduce the levels of somatic instability – perhaps delaying symptom onset or disease progression.

– There are now numerous companies seeing if they can make medicines to stop CAG repeats from expanding or even shrink repeats by targeting the process of somatic instability.

One is LoQus23 Therapeutics, another is Triplet Therapeutics

– Both companies hope that by impairing the actions or reducing levels of specific proteins involved in DNA repair, they can stop or slow somatic instability and therefore delay symptom onset or progression, Dr Rachel Harding and Dr Leora Fox states.


Learn more by taking a look at some of the research talks presented to families at HDSA’s 2020 Virtual Convention, summarised here